Abstract We propose to develop analogs of human complement C3 that have the ability to form a stable C3 convertase. In addition, these proteins will be designed to decrease the affinity of the proteins for factor H binding. All proteins will be expressed in the Baculovirus insect protein expression system, and tested for their ability to form a stable C3 convertase enzyme that is able to deplete complement in human serum. They will also be tested for their resistance to cleavage by complement factors H and I. Proteins that can form stable and active C3 convertases that are resistant to cleavage by complement factors H and I will be tested in in vitro pharmacokinetics, stability, and aggregation studies. In Phase II of this application, we will test these proteins for their ability to protect PNH erythrocytes against lysis, and in animal models. We will also commence GMP production of the protein and initiate IND-enabling development, including preclinical immunogenicity assessment, to prepare for Phase I clinical trials.